Genetic Risk Assessment for CancerJennifer Siettmann, MS CGC

Certified Genetic Counselor/Cancer Risk CounselorBanner Good Samaritan Cancer Screening & Prevention Program

Objectives

• Describe the role of genetic counseling and genetic testing in patient care

• List indications for referral for hereditary cancer genetic testing

• Describe features of common hereditary cancer syndromes

• Describe the genetic testing process and new testing advancements

Genetic Predisposition Testing is a Multistep Process

Identify at-risk patients

Provide pretest

counseling

Provide informed consent

Select and offer test

Disclose results

Provide post-test

counseling and

follow-up

Who is at High Risk for Hereditary Cancer?

• Hereditary cancers account for only a small portion of all cancer.– Only about 5‐10%

• Important to elicit cancer family history to determine who might be at risk– Personal history of cancer– Family history of cancer

Distribution of Cancer

When to Expect a Hereditary Cancer Syndrome• Cancer in two or more close relatives (on same side of family)• Early age at diagnosis (<50)• Multiple primary tumors in the same individual• Bilaterality or multiple rare cancers• Pattern of tumors consistent with specific cancer syndrome 

(e.g. breast and ovary)• Evidence of autosomal dominant transmission

– Multiple affected generations

• Presence of congenital anomalies or syndrome‐associated benign lesions

Suspicious Genetic Cancers

Andrea Forman, Fox Chase Cancer Center

Rare Tumors That Warrant Genetic Evaluation• Adrenocortical Carcinoma (Tp53)• Carcinoid Tumors (specifically thymic gland) (MEN1)

• Diffuse Gastric Cancer (CDH1)• Fallopian Tube/Primary Peritoneal Cancer (BRCA1/BRCA2)• Leiomyosarcoma (FH)

• Medullary Thyroid Cancer (RET)• Paraganglioma (SDHA, SDHB, SDHC, SDHD, SDHAF2)

• Pheochromocytoma (SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1)

• Chromophobe or Oncocytoic Renal Cell Cancer (FLCN)• Sebaceous Neoplasms/Carcinomas (MLH1, MSH2, MSH6, PMS2, 

EPCAM)• Sex Cord Tumors with Annular Tubules (STK11)

*Banks, et al. 10 Rare Tumors that Warrant a Genetics Referral. Fam Cancer. Epub 2012, Nov 28.

Common Cancer SyndromesSyndrome Gene CancerRetinoblastoma RB1 Retinoblastoma

Li‐Fraumeni P53 Breast, brain, bone

FAP APC Polyps, colon, thyroid

Lynch MLH1, MSH2, MSH6, PMS2 Colon, uterine, ovarian, GI

Breast and Ovarian BRCA1 and BRCA2 Breast, ovarian

Von Hippel Lindau VHL Renal, pheo

Cowden PTEN Breast, uterine, thyroid

HDGC CDH1 Diffuse gastric, lobular breast

MEN2/FMTC RET Thyroid

Hereditary Melanoma CDKN2, CDK4 Melanoma

Hereditary PGL/PCC SDHB, SDHD Pheo, paraganglioma

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)• Caused by mutations in the BRCA1 and BRCA2tumor suppressor genes

• Incidence: 1 in 4,000– 1 in 40 in Ashkenazi Jewish families

• Features:– Early onset breast cancer (under age 50)– Ovarian cancer– Bilateral breast cancer– Male breast cancer– Ashkenazi Jewish heritage

HBOC Lifetime Cancer Risks

Lynch Syndrome

• Caused by mutations in mismatch repair genes MLH1, MSH2, MSH6, and PMS2

• Features:– Early age of colon cancer diagnosis (~45 years)– Right‐sided cancers– Cancers outside the colon:

• Uterine/Endometrial• Ovarian• Stomach, small bowel, urinary tract, bile ducts, brain, pancreas

Lynch Syndrome Lifetime Cancer Risks

GeneralPopulation

MLH1 and MSH2

Mutation

MSH6 Mutation

PMS2Mutation

Colon 5.5% 40‐80% 10‐22% 15‐20%

Endometrial 2.7% 25‐60% 16‐26% 15%

Stomach <1% 1‐13% <3%

Combined Risk of 6%

Ovarian 1.6% 4‐24% 1‐11%

Bile Duct <1% 1.4‐4% Not reported

Urinary Tract <1% 1‐4% <1%

Small Bowel <1% 3‐6% Not reported

Brain/CNS <1% 1‐3% Not reported

Sebaceousneoplasms

<1% 1‐9% Not reported Not reported

Pancreas <1% 1‐6% Not reported Not reported

IHC Testing for Lynch Syndrome

MLHI

MSH2

MSH6

PMS2

Normal Suspicious of Lynch

Genetic Predisposition Testing is a Multistep Process

Identify at-risk patients

Provide pretest

counseling

Provide informed consent

Select and offer test

Disclose results

Provide post-test

counseling and

follow-up

Pretest Genetic Counseling

• Assess– Personal and family medical history– Risk perception and motivation for testing

• Educate– Basic genetics and inheritance– Cancer genetics and risk

• Discuss– Risks, benefits, and limitations of testing – Test procedure– Alternatives to testing– Management options

Pretest Genetic Counseling

• Anticipatory guidance– Cancer genetics professionals should walk the patient through “what if” scenarios

• Consideration of multiple motivations for testing– Why does the patient want to be tested?– What does he or she hope to accomplish?

• Informed consent discussion

Creating a Family History or Pedigree

Basic Genetics

Inheritance: Typically Autosomal Dominant

Genetic Predisposition Testing is a Multistep Process

Identify at-risk patients

Provide pretest

counseling

Provide informed consent

Select and offer test

Disclose results

Provide post-test

counseling and

follow-up

Genetic Testing Panels• Old method: test for one syndrome/gene, if negative, go on to 

next…• New method: genetic testing panels

– Test for multiple hereditary syndromes/genes at one time– Lower costs– Results can be much more difficult and confusing to interpret

• Options for cancer specific panels (i.e. breast vs colon vsgynecologic) and varying sizes within those panels

• The difficulty comes from knowing which panel to order for which patient’s history, how many genes we want to test, and what the clinical efficacy is of each of the genes on the panel– Some genes are high risk genes, whereas others are moderate risk 

genes

Example of a Breast Cancer Panel

High Risk Genes Moderate Risk Genes

Newer Moderate Risk Genes

Genes BRCA1, BRCA2, CDH1, PTEN, STK11, 

TP53

ATM, CHEK2, PALB2, NF1

BARD1, BRIP1,MRE11A, MUTYH, NBN, RAD50, 

RAD51C, RAD51D

Lifetime Breast Cancer Risk

50‐85% 20‐50% 20‐40%(not well defined)

Medical Management

Established guidelines for screening and prevention.

Cancer risk consistent across 

families.

Guidelines mostlyestablished.

Cancer risk may vary based on family history. 

Guidelines not established.

Manage based on family history and estimated cancer 

risk.

Genetic Predisposition Testing is a Multistep Process

Identify at-risk patients

Provide pretest

counseling

Provide informed consent

Select and offer test

Disclose results

Provide post-test

counseling and

follow-up

Understanding Possible Test Results

No Increased Cancer Risk

Cancer Risk Not Fully Defined

Unknown Cancer Risk

Increased Cancer Risk

NegativeResult

NegativeResult

Variant ofUncertain

Significance

Known Family Mutation

No Known Family Mutation

Positive Result

High-Risk Clinical Management

Cancer Detection & Risk Reduction Options

Notifying at-riskrelatives

Increased Surveillance

Chemoprevention Risk Reduction Surgery

LifestyleChanges

Cost and Insurance

• Average test costs between $1500 to $4400 (depending on the panel and the lab)

• Insurance coverage pretty good if patient meets National Comprehensive Cancer Network (NCCN) guidelines

• Each insurance carrier has their own criteria, some are publicly available (Aetna, UHC, Medicare, BC/BS) some are not (Medicaid, Banner)

• Coverage of panel testing has been reliable so far so long as the patient meets criteria for Lynch or BRCAtesting

Genetic Discrimination

• In 2008, a federal law called the Genetic Information Nondiscrimination Act (GINA) was passed– Prevents health insurance 

and employers from discriminating based on genetic test results

– Doesn’t apply to life insurance or long‐term disability

– Doesn’t apply to the military

Case Example 1: KM

• KM breast cancer @ 47– Mother: Br.Ca @ 28 

Died of Ov. Ca. @ 37– Maternal Aunt: Br. Ca @ 50– Maternal Aunt: Br. Ca. @ 58– Maternal Grandma: Br. Ca died in 

50s– Father: Lung Ca @ 73

• European descent both sides

Case Example 1: KM

Case 1: KM Test Results and Plan• Test Result: Positive for a BRCA2mutation

– Up to 85% risk for breast cancer• 60% Risk for second primary

– Up to 40% risk for ovarian/fallopian tube cancer– 6% risk for Male breast cancer

• Prevention Method– Bilateral salpingo‐oophortectomy– Bilateral mastectomy 

• Family Prevention– Offer testing and high risk prevention options to all close family members

Case Example 1: KM

Case Example 2: PA

• PA is a 65 y.o. woman diagnosed with uterine cancer @ 61 and bladder cancer @ 65– Sister: pancreatic @ 64– Mom: colon @ 56– Maternal aunt: colon @ 89– Maternal aunt: ovarian– Maternal cousin: colon in 40s

• European descent on both sides

Case Example 3

Case 2: PA Test Results and Plan• Ordered a panel for 32 cancer genes• Test Result

– Positive for a MSH6 mutation• Up to 22% risk for colon cancer• Up to 26% risk for uterine cancer• Up to 11% risk for ovarian cancer• Increased risk for stomach, urinary tract, and possibly breast cancers

– Variant of uncertain significance (VUS) in NBN• True mutations associated with moderately increased risk for breast and ovarian 

cancer

• Prevention Method:– Colonoscopy every 1‐2 years beginning age 25‐30– Patient already had hysterectomy and bilateral salpingo‐oophorectomy– No screening is recommended for the NBN VUS as it is an inconclusive 

result and we cannot make recommendations for an inconclusive result

• Family Prevention:– Offer testing and high risk prevention options to 

all close family members

Case Example 3: BB

• BB diagnosed with breast cancer @ 49– Mother: breast @ 76– Maternal aunt: breast @ 44– 2 maternal uncles: brain @ 56 and 64

– Paternal aunt: breast– Paternal cousin: breast @ 44– Paternal grandma: breast @ 31

• European descent on both sides

Case 3: CD Test Results and Plan• Ordered a panel for 17 breast cancer genes• Test Result:

– Positive for a Tp53 mutation, responsible for Li FraumeniSyndrome

• 50% risk for any type of cancer by age 40• 90% risk for any type of cancer by age 60

Breast, 24Bone, 12.6

Brain, 12Sarcoma, 11.6

GI, 7Gynecologic, 5.3

Hematologic, 4.2Adrenal, 3.6

Other, 14.1

0 5 10 15 20 25 30

Tumor Types

Percent of Tumors (%)

Case 3: CD Test Results and Plan• Prevention Method

Cancer 0‐1 Years

General Biannual physical exam (neurological, thyroid)Avoid radiation treatment when possible

Adrenocortical and Sarcoma Annual Testosterone levels

Annual WB‐MRI*

Brain Annual brain MRI*

Leukemia Annual CBC, Erythrocyte labs

Melanoma Annual dermatologic exam

Breast (begin at 25) Biannual clinical breast exam

Annual MRI and mammogram

Consider prophylactic mastectomy

Colon (begin at 25) Colonoscopy and upper endoscopy every 2‐5 years

Ovarian (begin at 35) Biannual CA‐125 and transvaginal U/S

Consider removing ovaries and uterus

Questions?

phone: 602-839-6385jennifer.siettmann@bannerhealth.com